Recently we have re-evaluated MED caused by mutations in the type IX collagen genes (COL9-MED), in part due to our recent revision of the MED GeneReviews Article.
COL9-MED is generally the mildest form of MED and is characterized by joint pain and stiffness presenting in the first decade of life, whilst radiographic abnormalities are primarily restricted to the knees with relative sparing of the hips.
In our most recent 7-year study we concluded that MED resulting from mutations in the type IX collagen genes was the rarest form and accounted for the less than 10% of all genetically confirmed MED. Most of the mutations were in the gene encoding the alpha2(IX) chain (COL9A2). Indeed, of the 22 known mutations that I am aware of (through publications or our own research) they break down as follows:-
- COL9A1 = 1 family
- COL9A2 = 15 families
- COL9A3 = 6 families
Now that’s not to say that more mutations have not been found by various diagnostic labs around the world, but currently that information is not available.
What is the geographical distribution of COL9A2-MED?
Although it was proposed in 2006 that COL9-MED was more prevalent in Japan, I just don’t think that the numbers justify this claim. Of the 15 families with confirmed COL9A2-MED; 12 are of Northern European descent and breakdown as follows [UK (4); Netherlands (4); Germany (3); and unspecified (1)]; the remaining 3 are from Korea or Japan.
But, I’m not saying that COL9A2-MED is specific to Europe, because clinical ascertainment and access to genetic testing may be influencing this distribution.
COL9A2-MED mutations show an interesting distribution across Europe.
The COL9A2 mutations that have been identified to date are all in the splice-donor site of exon 3. Seven different COL9A2-MED mutations have been found in Europe and these are listed as follows (along with their EU distribution):-
- c.186 G>A [Germany = 2]
- c.186 G>C [Germany = 1]
- c.186+2 t>c [Netherlands = 4]
- c.186+2 t>a [UK = 1]
- c.186+4 a>c [UK = 1]
- c.186+5 g>c [UK = 1]
- c.186+6 t>g [UK = 1]
The numbers are small so any conclusions have to be taken with a pinch of salt, but it would seem that there is at least one Dutch COL9A2 ‘ancestral’ mutation (c.186+2 t>c), whereas the British families all have different mutations. Two mutations so far account for COL9A2-MED in German families.
But what now?
Despite our best research efforts we still know the least about MED caused by type IX collagen mutations. We do know that the COL3 domain of type IX collagen is important because that is where all the mutations are clustered and result in its deletion from the mature protein. The development of relevant model systems is the only way that we will make progress in understanding disease mechanisms.
MED is rare, and COL9-MED is rarer still, particularly if half of the cases in Europe are due to an ancestral mutation. Are we looking at 1 in 100-200,000 people?